Viruses with linear, dsDNA genomes, such as the adenoviruses (Ad) and herpesviruses, encounter a number of host cell responses that may severely inhibit virus replication. The open ends of the linear viral genomes trigger a cellular DNA damage response (DDR). A DDR severely inhibits Ad DNA replication if unabated. The major Ad core protein, protein VII, protects the viral genome from recognition by the DDR immediately after infection. As protein VII is released from the Ad genome during the early phase of viral infection, Ad inhibits a DDR by alternative mechanisms to allow efficient viral replication. Core protein VII is tightly associated with the viral genome within the Ad virus particle, the capsid. It is not clear how protein VII is packaged into the Ad capsid during virus assembly. A means to conditionally express Ad core protein VII during viral infection has been developed. This approach will be used to study the functions of Ad core protein VII during all aspects of the virus replication cycle. These studies pertain not only to Ad, but to more complex dsDNA viruses such as the herpesviruses. Ads have been recognized in recent years as significant pathogens in immunocompromised patients. Ad infection is also associated with severe respiratory disease in the young, elderly, and in military personnel. There is no virus-specific therapy for Ad infection. Thus, it has become increasingly important to fully understand the Ad replication cycle in order to foster the development of antiviral therapies. PUBLIC HEALTH RELEVANCE: This research focuses on early and late events during adenovirus replication. Adenoviruses have been recognized in recent years as significant pathogens in immunocompromised patients. There is no virus-specific therapy for adenovirus infection, thus it has become increasingly important to fully understand the virus replication cycle in order to foster the development of antiviral therapies.